5-phenyl-5(3-thienyl)-hydantoin and salts thereof



United iPamT 5-PZ-lENYL-5(3-TIHENYL)-HYDANTOIN D SALTS THEREOF Ernest E. Campaigne, Bloomington, Ind., assignor to Indiana University Foundation, Monroe County,'Ind.,

- acorporation of ndiana V No Drawing. Application November 19, 1 9512 Serial-No. 321,500 Y 3Claims. C1. 260-3095) This invention relates to a new compound, 5 phenyleth'er solution wasconcehtrateid and the residue was dis-1 I tillefd.) After. being, cooled-inf anfiacetone-dry ice ,bath the product .clrystallizedfromfmethanol; giving. 6:9 g. (56%) of}phenyl-3-thienyl ketone; M. 11163-64 C. Analg Calc'd; fo'rlCii-HsOSr-z S, "17.03. Fo'undrpS,

C., when recrystallized from dilute ethanol. 15'.

-(3-thienyl)hydantoin, to non-toxic salts thereof, and .f

to a method for its preparation.

My new compound has anticonvulsant properties. and

has surprisingly been found to be considerably more active and less toxic than the isomeric 5-phenyl-5-(2- thienyl)hydantoin when tested in rats by the electroshock method. For example, 5-phenyl-5-( 3-thienyl)hydantoin has a minimum effective dose of mg. per kg. of body weight and a minimumtoxic dose of 250mg. per kg.

' solidproduct was-collectedby-:filtration and, recrystallized fromidiluite acetic acid, usingactivatedcharcoal.for

decolorizing purposes, to givje 4.2 g." (67% of. S-phenyl- 5-phenyl-5-(3-thienyl)hydantoin is' useful per seas an I anticonvulsant. Howeventhis compound, like 'oth crhy-v dantoins unsubstituted in the 3-position, poss'esses an'.

acidic hydrogen and is readilyconverted to salts "by ref action with inorganic or organic bases, and those' s alts J whose cations are non-toxic to the animal organism' are likewise useful as anticonvulsants. Particularly useful are the salts derived from'alkali' metal and alkali earthmetal hydroxides, such as the sodium, potassium and calcium salts; the ammonium salt; and salts derived from organic amines and diamines, such as the ethanolamine, diethanolamine and ethylenediamine salts.

The following example will vention.

EXAMPLE (a) Phenyl 3-thienyl ketone: Asolution of 47.1 g.

further illustrate the in- H I v c'a'lform'ula' (0.3 mole) of freshly distilled bromoben zene in ;cc..

of dry ether was gradually added to 5.0 'g. (0.206 mole) of magnesium filings (30 mesh) under 250 cc. of dry. ether. After the preparation of the Grignard reagent was complete, there was added slowly, with stirring, 7.2

g. (0.066 mole) of 3cyanothiophene in 50 cc. of dry ether at such a rate as to keep the solutionrefluxing slowly. ing for an hour after the addition of the 3-cyanothiophene was completed, andthen the mixture was heated The refluxing continued without outside heat- 3L" Inthe process'forlpreparing 5-phenyl'-5-(3-thienyl)- hydantoin, the step lwhich'comprises heating phenyl 3- thienyl ketone withan excess of analkalimetalcyanide,

of ammonium carbonate in an inert sol-" I p *vent- I to continue the refluxing for another three hours and allowed to stand overnight. The mixture was hydrolyzed by the addition of flaked ice, followed by'dilute sulfuric acid until the basic salts had dissolved. The remaining yellow solid was collectedby filtration and'shaken with f Patented June- 21, 1955 was separated, the waterlayer was extracted twice with 3 ether, and the combined etherj extractsgwere washed with 1 water and dried over anhydrous magnesium sulfate. The

The. semicarbazone of phenyl S-thicnyI 'ketOne, pr'eQ pared from 0.2 g..of 'ketone, 0.2 g. of ser nicarbazide=-hy-.,

.drochloride and 0.3 g. of sodium acetate in dilute ethanol" solution, was obtained as whitefneedles, M.-121178 179? crystallized from chloroform.

g (b) 5-phenyl-5-(3-thienyl)hydantoin;IA mixture of p 4.6 g. (0.0245 mole) of'phenyl 3-thienylfketone, 4;8 g. (0.0735 mole) of potassium cyanide .and 9.4g. (0;09 I

mole) ofammonium carbonate in cc, of 60% ethyl alcohol was heated in seemed tube Carius furnace 1; 5 at C. for ninety hours. The tubWas cooled and f 1 opened, and the reaction mixture. was" carefully poured, 7

into 200 cc. offwater. The mixture'was then-acidified under an, efiicient hood and the resulting precip'itatelwas collected 'by filtration; The solid wasbdiss'olved in,,5%f

sodium hydroxide solution-,- {and the 1' alkaline; solutio n containing the sodium; salt of 5ephenylr5-(3 -thienyl)hyj dantoinwas acidified with dilute-hydrochloric acid. ;The

5-(3-thienyl)hydantoin, 254

.AnaL-Calcd. forCraI-Irb'OzNgS; 3,112.41; N, 10.35..

13A member of the gro p;.chnsisting ofI 5 phenyl-5.Ll (3-thienyl) hydantoin havingjthe chemical formula GoHa l p 7' o=o NH" 3 i I 5 V H s, alt-i=0 and non-toxic salts thereofa. 2. 5-phe'nyl-5-(3-thi nyl) hydantoin and an excess References file of patent UNITED: STATES PATENTSG OTHERKREFERENCES" 6N sodium hydroxide solution and ether- The ether layer 7 bar, Ind. parfum, vol,' 2, pp. 193 511947);

The" 2,4-dinitrophenylhydrazone -of phenyl 3 -thienyl "ketoneprepared by heatingjOZ g. of'keto'ne; 0.2 g. of I 1 dinitrophenylhydrazine and.0.2 ccf'of concentrated by drochloric acid in 10 cc. of 95% ethyl alcohol, was 'ob- [1,1 tained as orange needles, M. P. l2l1211.5; C., when re-. 7,

having the chemi- 

1. A MEMBER OF THE GROUP CONSISTING OF 5-PHENYL-5(3-THIENYL) HYDANTOIN HAVING THE CHEMICAL FORMULA 